Dual FDG/PSMA PET imaging to predict lesion-based progression of mCRPC during PSMA-RLT

Candidates for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) frequently have “mismatch” lesions with pronounced 18-fluorodeoxyglucose ([18F]FDG) but attenuated PSMA ligand uptake on positron emission tomography (PET). However, no quantitative criteria yet exist to identify mismatch lesions and predict their response to RLT. To define such criteria, we retrospectively analyzed 267 randomly-selected glucometabolic mCRPC metastases from 22 patients. On baseline PET, we determined [18F]FDG and [68Ga]Ga-PSMA-11 maximum standardized uptake value (SUVmax), and calculated the [18F]FDG SUVmax/[68Ga]Ga-PSMA-11 SUVmax quotient (FPQ). From follow-up [18F]FDG PET after two lutetium-177-PSMA-617 RLT cycles, we evaluated the treatment response and categorized the lesions into three subgroups (partial remission, stable disease, progression) based on change in [18F]FDG SUVmax. Lastly, we compared the baseline PET variables in progressing versus non-progressing lesions. Variables differing significantly, and a score incorporating them, were assessed via receiver operator characteristic (ROC) curve analysis, regarding ability to predict lesional progression, with area under the curve (AUC) as metric. Cut-offs with optimal sensitivity and specificity were determined using the maximum value of Youden's index. Fifty-one of 267 lesions (19.1%) progressed, 102/267 (38.2%) manifested stable disease, and 114/267 (42.7%) partially responded after two RLT cycles. At baseline, median [68Ga]Ga-PSMA-11 SUVmax was significantly lower (p < 0.001), median FPQ significantly higher (p < 0.001), and median [18F]FDG SUVmax similar in progressing versus non-progressing lesions. [68Ga]Ga-PSMA-11 SUVmax and FPQ showed predictive power regarding progression (AUCs: 0.89, 0.90). An introduced clinical score combining both further improved predictive performance (AUC: 0.94). Optimal cut-offs to foretell progression were: [68Ga]Ga-PSMA-11 SUVmax < 11.09 (88.2% sensitivity, 81.9% specificity), FPQ ≥ 0.92 (90.2% sensitivity, 78.7% specificity), clinical score ≥ 6/9 points (88.2% sensitivity, 87.5% specificity). At baseline, a low [68 Ga]Ga-PSMA-11 SUVmax and a high FPQ predict early lesional progression under RLT; [18F]FDG SUVmax does not. A score combining [68 Ga]Ga-PSMA-11 SUVmax and FPQ predicts early lesional progression even more effectively and might therefore be useful to quantitatively identify mismatch lesions.


Endpoints
The first endpoint was each lesion's uptake of [ 68 Ga]Ga-PSMA-11 and of [ 18 F]FDG, reflected by the maximum standardized uptake value (SUV max ) of each radiotracer, on PET scans acquired before [ 177 Lu]Lu-PSMA-617 RLT, i.e. at baseline.As part of this endpoint, we also calculated the pre-RLT [ 18 F]FDG SUV max /[ 68 Ga]Ga-PSMA-11 SUV max quotient (FPQ) for each individual lesion.
The second endpoint was the evaluation of each lesion's response to two RLT cycles, based on changes in the [ 18 F]FDG SUV max between the baseline [ 18 F]FDG PET/CT scan and a follow-up [ 18 F]FDG scan acquired after the second cycle.
The third endpoint was the comparison of baseline [ 68 Ga]Ga-PSMA-11 SUV max , baseline [ 18 F]FDG SUV max , and baseline FPQ in the subgroup of progressing lesions versus the subgroup of lesions with disease stability or partial response after the two RLT administrations, and determination of adequate cut-off values of these variables to predict lesional outcome.
The last endpoint, based on these comparisons, was the development and preliminary assessment of a score to use baseline quantitative PET variables to predict whether a lesion would progress early in the course of RLT.

Lesions, patients, and ethics
The analysis included a sample of [ 18 F]FDG-positive lesions in consecutive eligible patients with mCRPC who received two cycles of [ 177 Lu]Lu-PSMA-617 RLT.Eligible patients had to have available PET imaging data from three scans: (1) baseline (pre-RLT) [ 68 Ga]Ga-PSMA-11 PET/CT, (2) baseline [ 18 F]FDG PET/CT, and (3) followup [ 18 F]FDG PET/CT acquired shortly after completion of the two RLT cycles (Fig. 1).All patients received [ 177 Lu]Lu-PSMA-617 RLT within a prospective patient registry (REALITY Study, NCT04833517).The analyzed imaging and treatment took place at the Saarland University Medical Center between 21 January 2019 and 21 December 2022.The selection of [ 18 F]FDG-positive target lesions was random and did not consider uptake in PSMA ligand PET/CT.
A total of 267 lesions from 22 men (up to 14 per patient) were included in this analysis.Table 1 shows characteristics of the lesions and of the study sample.The analyzed lesions were mostly (almost 80%) in the skeleton.The patients tended to have late-stage or end-stage disease and were heavily pretreated.They received the PSMAtargeted RLT on a compassionate use basis according to §13 (2b) of the German Pharmaceutical Act.Patients gave written informed consent, which also covered participation in the registry and permission for de-identified patient data to be published in scientific communications.The study was approved by the local institutional review board (ethics committee approval number 140/17, 13 July 2017).]FDG (follow-up scan) were given.Patients fasted at least 4 h before each [ 18 F]FDG infusion, and were instructed to void shortly before all PET/CT scans.Imaging was carried out applying standard protocols 35,36 .Whole-body PET images were acquired from vertex to mid-femur, using 3 min ([ 68 Ga]Ga-PSMA-11) or 2 min ([ 18 F]FDG) per bed position, with a 21.4-cm extended field-of-view.A Biograph 40 mCT scanner (Siemens Medical Solutions, Knoxville, TN, USA) was employed.For attenuation  correction and anatomical localization, low-dose CT was performed together with the PET, using a 120-keV X-ray tube voltage.The tube current was modulated with CARE Dose4D software (Siemens Healthineers, Erlangen, Germany), with 30 mAs as the reference.PET datasets were reconstructed with an iterative 3-dimensional ordered-subset expectation maximization algorithm (3 iterations, 24 subsets) with gaussian filtering (5 mm full width at half maximum) and a 3 mm slice thickness.Besides attenuation correction, random, decay, and scatter correction were done.

PET/CT data analysis
Firstly, [ 18 F]FDG-positive target lesions of mCRPC were randomly selected and analyzed at baseline [ 18 F]FDG PET/CT.Subsequently, the same target lesions were analyzed on the baseline [ 68 Ga]Ga-PSMA-11 PET/CT scan.Care was taken to exclude foci representing characteristic inflammatory changes on [ 18 F]FDG PET/CT, e.g.pulmonary inflammatory changes or reactive-inflammatory lymph nodes.For each target lesion and both radiotracer SUV max was quantified, applying Syngo.via(Siemens Healthineers, Erlangen, Germany).In addition, FPQ was calculated for each individual lesion by dividing SUV max of [ 18 F]FDG by SUV max of [ 68 Ga]Ga-PSMA-11.

RLT response classification
For each target lesion selected on baseline [ 18 F]FDG PET/CT, SUV max was analyzed on the follow-up scan after two cycles of [ 177 Lu]Lu-PSMA-617 RLT.Response to the two cycles of [ 177 Lu]Lu-PSMA-617 RLT was classified based on the change in lesional SUV max (i.e., radiotracer uptake) from the baseline [ 18 F]FDG scan to the followup [ 18 F]FDG scan.Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 37 were used.
According to these criteria, a ≥ 30% decrease from baseline SUV max was defined as a partial response, a < 30% decrease to a < 30% increase, as stable disease, and a ≥ 30% increase, as progression.

Statistics
Descriptive statistics are reported as mean ± SD, median (minimum-maximum), and/or number (percentage) or vice versa, as applicable.The Mann-Whitney-U test was used to compare baseline SUV max of each radiotracer and baseline FPQ between the subgroup of lesions progressing after RLT versus the subgroup of non-progressing lesions, i.e. those exhibiting stable disease or partial response.Statistical significance was set at p < 0.05.All statistical analyses were carried out using Prism version 8 (GraphPad Software, San Diego, CA, USA).Variables showing a significant difference between lesion response subgroups were used to develop a lesion response prediction score for clinical application.For this score, points were assigned for different values of the respective variables with the goal of achieving a stepwise increment in lesional progression risk as the score increased.
Receiver operator characteristic (ROC) curve analysis was carried out to assess predictive performance of the significant variables and of the score.The perfomance metric was the area under the ROC curve (AUC).For each variable and for the predictive score, the maximum value of the Youden's index (J) was used to determine the cut-off that attained optimal sensitivity and specificity.

Ethics approval and consent to participate
All procedures performed in the patients described herein were in accordance with the ethical standards of the Institutional and/or National Research Ethics Committees and with the 1964 Helsinki Declaration and its later amendments, or with comparable ethical standards.This analysis was approved by the Institutional Review Board of the Ärztekammer des Saarlandes/Saarbrücken (approval number: 140/17, approval date: 13 July 2017.This report does not include any animal studies.Written informed consent was obtained from all participants.
On ROC curve analysis, baseline [ 68 Ga]Ga-PSMA-11 SUV max and baseline FPQ showed similar performance to discriminate between lesions that would progress after two RLT cycles versus lesions that would not: respective AUCs were 0.89 versus 0.90.The respective maximum values of the Youden's index (J) identified a baseline [ 68 Ga] Ga-PSMA-11 SUV max of < 11.09 (Fig. 6A) or a baseline FPQ of ≥ 0.92 (Fig. 6B) as the threshold values of these variables that had optimal sensitivity and specificity in distinguishing lesional progression versus non-progression.A clinical score incorporating the two variables, the dual imaging progression prediction (DIPP) score, was developed (Fig. 7A).Using ROC curve analysis, the DIPP score achieved an AUC of 0.94 to predict lesional response (Fig. 7B).The maximum value of the Youden's index (J) determined a DIPP score ≥ 6 on the 0-9point scale to be the optimal threshold denoting high risk of lesional progression.With 88.2% sensitivity and 87.5% specificity (OR 52.5), this DIPP score threshold appeared to have comparable sensitivity, but appreciably improved specificity, relative to each of its component variables at their optimal thresholds.

Discussion
This study is, to our knowledge, the first yet published that addresses the unmet need for lesion-based quantification of mismatch, by analyzing the relationship of baseline [ 68 Ga]Ga-PSMA-11 and baseline [ 18 F]FDG PET variables to RLT response, and introducing a scoring system that appears to effectively predict early lesional progression.
Our key finding was that efficient prediction of lesional response to RLT may be provided by considering not just the "traditional" eligibility criterion of PSMA ligand uptake, i.e.SUV max , but an additional PET variable, the FPQ, i.e. the ratio of [ 18 F]FDG SUV max to [ 68 Ga]Ga-PSMA-11 SUV max .Even better prediction may be achieved by using the DIPP score introduced here, which combines these two variables, and which can be easily and quickly calculated.

Characteristic/finding Value
Lesional Thus, our analysis furnishes additional evidence buttressing use of [ 18 F]FDG PET/CT in screening candidates for PSMA-targeted RLT.However, our study also supplies evidence supporting the (unsurprising) primacy of PSMA ligand uptake in predicting lesional response to PSMA-targeted RLT.We noted that baseline [ 18 F]FDG SUV max alone did not differ between progressing and non-progressing lesions.By contrast, baseline [ 68 Ga]Ga-PSMA-11 SUV max was a strong predictor of lesional progression to PSMA-targeted RLT both by itself (at a cut-off of < 11.09, 88.2% sensitivity and 81.9% specificity) and as part of the FPQ (at a cut-off of ≥ 0.92, 90.2% sensitivity and 78.7% specificity).Moreover, considering PSMA ligand uptake as an absolute value as well as a relative value (i.e. as the denominator of the FPQ), combined into the DIPP score, further strengthened predictive performance (at a cut-off of ≥ 6/9 points, 88.2% sensitivity and 87.5% specificity).
Also of interest, there was an 80% rate of lesional stable disease or partial response in our study, notwithstanding the high degree of glucometabolism in many of the analyzed lesions.These observations support the notion that RLT may be beneficial even in lesions with high [ 18 F]FDG uptake, so long as a sufficient proportion of cells has adequate PSMA expression-a factor that may be readily discerned using the FPQ.The benefit of RLT in such cases also has been suggested by others 29,43 .
A routine implementation of [ 18 F]FDG PET/CT in clinical practice to screen candidates for PSMA-targeted RLT certainly brings additional information compared with a (contrast-enhanced) diagnostic CT but may have to be weighed against the potential financial burden regarding additional costs.
Based on our data, a mismatch lesion with insufficient PSMA expression and potential resistance to PSMAtargeted RLT can be identified by using the variables PSMA PET-derived SUVmax and FPQ.Compared to [ 68 Ga] Ga-PSMA-11 SUV max or FPQ alone, a score combining both further strengthens predictive performance.We propose that a mismatch finding can be identified with a DIPP score of ≥ 6. Quantitatively indentifying mismatch lesions may facilitate individualized decision-making regarding PSMA-targeted RLT and the design of individualized mCRPC management strategies.However, the feasibility of implementing the DIPP score into clinical routine needs to be evaluated.We recommend studies, ideally prospective, in larger patient cohorts verifying our observations and addressing the clinical impact of this approach.
This analysis has several limitations.Firstly, the retrospective, single-center study design may impose bias and decrease generalizability and transferability.Other cutoff values would be expected for the use of different PSMA ligands or other reconstruction settings.Secondly, a possible selection bias cannot be excluded, as only a (pre-)selected number of patients who participated in the REALITY study received baseline and follow-up [ 18 F] FDG PET/CT.The results of the present study should be treated with caution when compared with outcome data from other studies as our criterion of lesional progression was based on [ 18 F]FDG PET/CT which is not established for prostate cancer such as response based on PSMA PET/CT or structural changes as reflected by Response Criteria in Solid Tumors 44 .Furthermore, our definition of progression was formulated on a lesional basis, not a patient basis.Further studies should be undertaken to consider relationships of PSMA ligand uptake and [ 18 F]FDG uptake across the total tumor burden, e.g. in form of whole-body PET variables such as total lesion PSMA and total lesion glycolysis.These variables should be analyzed for their association with patient-based RLT response or overall survival.Lastly, we did not validate the DIPP score in a sample of lesions separate from those used to develop the score.The score's predictive performance should be confirmed in this way.

Figure 1 .
Figure 1.Schematic summary of study design.

Figure 7 .
Figure 7. (A) Dual imaging progression prediction (DIPP) score and (B) ROC curve showing the score's performance to predict lesional progression.The maximum value of the Youden's index (J) identified a DIPP score of ≥ 6 on a 0-9-point scale (sensitivity 88.2%, specificity 87.5%) as showing optimal predictive performance among DIPP score values. 18

Table 1 .
Characteristics of the patients cohort and target lesions.ADT androgen deprivation therapy, ECOG eastern cooperative oncology group, NAAD novel androgen access drugs, PSA, prostate-specific antigen.
18nclusionsA low baseline SUV max on [ 68 Ga]Ga-PSMA-11 PET/CT and high baseline FPQ, which incorporates the former as well as baseline [18F]FDG SUV max , predict lesional progression early in the course of RLT, whereas baseline [18F]FDG SUV max by itself does not.Compared to [ 68 Ga]Ga-PSMA-11 SUV max or FPQ alone, a score combining